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Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Mahnaz Sahraei, … , Carlos Fernández-Hernando, Yajaira Suárez
Published November 11, 2019
Citation Information: J Clin Invest. 2019;129(12):5518-5536. https://doi.org/10.1172/JCI127125.
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Research Article Angiogenesis Immunology

Suppressing miR-21 activity in tumor-associated macrophages promotes an antitumor immune response

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Abstract

microRNA-21 (miR-21) is the most commonly upregulated miRNA in solid tumors. This cancer-associated microRNA (oncomiR) regulates various downstream effectors associated with tumor pathogenesis during all stages of carcinogenesis. In this study, we analyzed the function of miR-21 in noncancer cells of the tumor microenvironment to further evaluate its contribution to tumor progression. We report that the expression of miR-21 in cells of the tumor immune infiltrate, and in particular in macrophages, was responsible for promoting tumor growth. Absence of miR-21 expression in tumor- associated macrophages (TAMs), caused a global rewiring of their transcriptional regulatory network that was skewed toward a proinflammatory angiostatic phenotype. This promoted an antitumoral immune response characterized by a macrophage-mediated improvement of cytotoxic T-cell responses through the induction of cytokines and chemokines, including IL-12 and C-X-C motif chemokine 10. These effects translated to a reduction in tumor neovascularization and an induction of tumor cell death that led to decreased tumor growth. Additionally, using the carrier peptide pH (low) insertion peptide, we were able to target miR-21 in TAMs, which decreased tumor growth even under conditions where miR-21 expression was deficient in cancer cells. Consequently, miR-21 inhibition in TAMs induced an angiostatic and immunostimulatory activation with potential therapeutic implications.

Authors

Mahnaz Sahraei, Balkrishna Chaube, Yuting Liu, Jonathan Sun, Alanna Kaplan, Nathan L. Price, Wen Ding, Stanley Oyaghire, Rolando García-Milian, Sameet Mehta, Yana K. Reshetnyak, Raman Bahal, Paolo Fiorina, Peter M. Glazer, David L. Rimm, Carlos Fernández-Hernando, Yajaira Suárez

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Figure 9

miR-21 expression by TAMs promotes tumor progression by inducing CD8+ T-cell suppression and angiogenesis.

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miR-21 expression by TAMs promotes tumor progression by inducing CD8+ T-...
(A–H) Tumor analysis of miR-21fl/fl and LysMCre;miR-21fl/fl mice with s.c. injection of LLCs (n = 7). LLC tumor volume (A), final tumor weight (B). (C) Left: Average % of TAMs of s.c. LLC tumors. Right: MHC II surface levels in TAMs (average MFI) (n = 6 out 7 randomly selected). (D) Left: Representative images of TUNEL and DAPI staining of cross sections of s.c. LLC tumors. Right: Quantification of % DAPI+ TUNEL+ cells (n = 7). (E) Flow cytometry analysis of CD8+ TILs in s.c. LLC tumors. Average % of CD8+ TILs (left), % of CD8+ TILs expressing GZMB (middle) and % of CD8+ TILs with extracellular CD107a (right) (n = 7). (F) Representative images of CD31 staining of cross sections of s.c. LLC tumors. Right: Quantification of CD31+ vessel-like structures (n = 7). (G) Average % CD31+ Ki-67+ cells of s.c. LLC tumors (n = 7). (H) Left: Representative images of immunofluorescence costaining of CD68 and CXCL10 in frozen sections of s.c. LLC tumors. Right: Average quantification of CXCL10 intensity per CD68+ cell (n = 3, out of 7 randomly selected). Results are mean ± SEM. *P < 0.05. (A) Two-way ANOVA (time and genotype) with Bonferroni correction, #P < 0.05 individual comparisons. (B–H) Mann-Whitney U test. (A–H) Representative experiment out of 2 with similar results. Scale bars: 70 μm.

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